cyclo(gln-trp-phe-gly-leu-met) and senktide

Substance P and related tachykinins are present in the mammalian gut and act as neurotransmitters. Microfluorimetric measurement of intracellular calcium ([Ca2+]i) was used to study tachykinin-sensitive myenteric neurons. Substance P (0.001-10 microM) evoked concentration-dependent increases in percentage of neurons responding (6-75%) and delta [Ca2+]i (88 +/- 24 to 212 +/- 16 nM). Neurokinin A (0.001-1 microM) produced similar responses. Removal of extracellular Ca2+ abolished substance P-induced Ca2+ signals, as did the addition of the Ca2+ channel blockers lanthanum chloride (5 mM) and nickel chloride (2.5 mM). Both nifedipine (1-50 microM) and diltiazem (1-50 microM) inhibited substance P-evoked Ca2+ responses in a dose-dependent manner. Substance P and related tachykinins evoke Ca2+ signaling in cultured myenteric neurons by the influx of extracellular Ca2+ through L and N-type plasma membrane Ca2+ channels.

Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Diltiazem; Dipeptides; Fluorometry; Guinea Pigs; Indoles; Lanthanum; Myenteric Plexus; Neurokinin A; Nickel; Nifedipine; Peptide Fragments; Peptides, Cyclic; Receptors, Tachykinin; Substance P; Tachykinins; Virulence Factors, Bordetella

1. The receptors involved in mammalian tachykinin-induced contractions of longitudinal smooth muscle strips of the rat gastric fundus were characterized pharmacologically. 2. Substance P (SP), neurokinin A, neurokinin B and senktide contracted the strips in a concentration-dependent manner with a potency order of neurokinin A > or = senktide > neurokinin B > substance P. The contractions were not influenced by tetrodotoxin and atropine. 3. L 659877, a NK2B-receptor-preferring antagonist reduced neurokinin A- and neurokinin B-induced contractions (estimated pKB 6.9 and 6.3, respectively) but had less pronounced effects on SP-induced contractions and none on contractions induced by senktide. MEN 10376, an NK2A-receptor-preferring antagonist, reduced the neurokinin A-induced contractions (estimated pKB 5.2), while dactinomycin, reduced the neurokinin A-induced contractions only to a minor extent at 10(-4) M. 4. CP 96345, an NK 1-receptor antagonist, reduced substance P- and neurokinin A-induced responses, but also reduced the contractions induced by KCl and methacholine. RP 67580, another non-peptide NK1-receptor antagonist had no effect on the substance P-, neurokinin A- and neurokinin B-induced contractions up to a concentration of 3 x 10(-6) M. 5. These results suggest that the mammalian tachykinins induce contractions of the longitudinal smooth muscle strip of the rat gastric fundus by direct action at muscular NK2B- and NK3-receptors.

Topics: Animals; Biphenyl Compounds; Dose-Response Relationship, Drug; Female; Gastric Fundus; Indoles; Isoindoles; Male; Methacholine Chloride; Muscle Contraction; Neurokinin A; Neurokinin B; Peptide Fragments; Peptides, Cyclic; Rats; Receptors, Tachykinin; Substance P; Tachykinins

Substance P (SP) has been shown to stimulate the hydrolysis of inositol phospholipids in peripheral tissues and in the brain. In mammalian peripheral tissues, three tachykinin receptor subclasses, neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3), have been identified. The purpose of our study was to pharmacologically characterize the SP receptors in the hypothalamus using phosphoinositide breakdown as a functional response. SP, previously described as a NK1 agonist, and Neurokinin A (NKA), previously described as a NK2 agonist, stimulated phosphoinositide breakdown in the hypothalamus in a dose-dependent fashion, with SP being more potent than NKA. The NK2-selective antagonist L-659,877, at a dose of 10(-6) M, abolished the effect of SP (10(-8) M) without affecting basal phosphoinositide breakdown. However, this NK2-selective antagonist did not inhibit the NKA-induced stimulation in phosphoinositide metabolism. The NK1-selective antagonist L-668,169 stimulated phosphoinositide metabolism at a concentration of 10(-6) M, but not at 10(-8) M. This NK1-receptor antagonist did not significantly inhibit the effect of SP on phosphoinositide metabolism. Spantide II, another NK1-selective antagonist, also stimulated phosphoinositide metabolism at a dose of 10(-6) M. Like L-668,169, spantide II failed to inhibit the SP-induced stimulation of phosphoinositide metabolism, and even potentiated the response to SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Carbachol; Dose-Response Relationship, Drug; Hypothalamus; In Vitro Techniques; Inositol; Male; Neurokinin A; Peptide Fragments; Peptides, Cyclic; Phosphatidylinositols; Rats; Rats, Wistar; Receptors, Neurokinin-1; Substance P; Tachykinins